# Plasmodium PfNCR1 uses a 141-residue HLH domain to reach narrow membrane contact sites

- Published: 2026-11-05 21:10 UTC
- Section: Life & Health › Biology & biochemistry
- Tags: PfNCR1, Plasmodium falciparum, malaria drug target, cholesterol homeostasis, membrane contact sites, HLH domain, amphipathic helix, Niemann-Pick C1-related protein, red blood cell
- URL: https://realtech.media/news/rt-91f9e81314fbcac6b443db4c_plasmodium_pfncr1_uses/

**Authors identified a helix-linker-helix domain unique to Plasmodium that localizes the cholesterol transporter PfNCR1, a drug target, to membrane gaps of about 3–4 nm.**

![Plasmodium PfNCR1 uses a 141-residue HLH domain to reach narrow membrane contact sites](https://sgzwpqqelzmajkcubgkl.supabase.co/storage/v1/object/public/rt-media/2026/11/495b402763a5d06b.jpg)
*Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, , Wikimedia Commons, Public domain*

A study in Proceedings of the National Academy of Sciences describes how PfNCR1, the Niemann-Pick Type C1-Related protein of the malaria parasite Plasmodium falciparum, reaches its working position at the interface with the host red blood cell. PfNCR1 facilitates cholesterol homeostasis there and is considered a promising anti-malarial drug target. [1] It localizes to regions covering about half of the host-parasite interface, which had been functionally uncharacterized. [1]

These regions are exceptionally narrow membrane contact sites, where only about 3–4 nm of vertical aqueous space remains between the membranes. [1] The authors set out to determine why PfNCR1 localizes there and what this means for cholesterol transport. The question also concerns a group of homologous proteins associated with congenital conditions and cancer.

## The HLH domain

The authors identified a 141-amino-acid domain unique to Plasmodium spp.: an amphipathic helix, a linker and a second amphipathic helix, termed the HLH domain. It is necessary for efficient localization of PfNCR1 to the narrow contact sites. [1] According to the authors, the localization relies on the physicochemical properties of the domain. [1]

GPI-anchoring of the isolated HLH domain was sufficient to target a fluorescent protein to the regions of endogenous PfNCR1. [1] The same held for a version in which the helices were replaced by the amphipathic helix of human ATG3. [1]

## Link to cholesterol transport

Functionally, the degree of PfNCR1 localization to narrow contact sites qualitatively correlated with its ability to maintain cholesterol homeostasis. [1] This connects the membrane contact of the protein with its recognized transport function. [1]

The authors conclude that the HLH domain is a key element for the localization and effectiveness of PfNCR1 in cholesterol transport, and that engineered proteins can be used to probe the narrow contact regions. [1]

## Sources

1. [Proceedings of the National Academy of Sciences](https://doi.org/10.1073/pnas.2621983123)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-91f9e81314fbcac6b443db4c_plasmodium_pfncr1_uses/